Subclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single-cell transcriptomics.

Abstract

Virtually all patients with multiple myeloma become unresponsive to treatment over time. Relapsed/refractory multiple myeloma (RRMM) is accompanied by the clonal evolution of myeloma cells with heterogeneous genomic aberrations and profound changes of the bone marrow microenvironment (BME). However, the molecular mechanisms that drive drug resistance remain elusive. Here, we analyze the heterogeneous tumor cell population and its complex interaction network with the BME of 20 RRMM patients by single cell RNA-sequencing before/after treatment. Subclones with chromosome 1q-gain express a specific transcriptomic signature and frequently expand during treatment. Furthermore, RRMM cells shape an immune suppressive BME by upregulation of inflammatory cytokines and close interaction with the myeloid compartment. It is characterized by the accumulation of PD1+ γδ T-cells and tumor-associated macrophages as well as the depletion of hematopoietic progenitors. Thus, our study resolves transcriptional features of subclones in RRMM and mechanisms of microenvironmental reprogramming with implications for clinical decision-making.

• Authors: Stephan M Tirier, Jan-Philipp Mallm, Simon Steiger, Alexandra M Poos, Mohamed H S Awwad, Nicola Giesen, Nicola Casiraghi, Hana Susak, Katharina Bauer, Anja Baumann, Lukas John, Anja Seckinger, Dirk Hose, Carsten Müller-Tidow, Hartmut Goldschmidt, Oliver Stegle, Michael Hundemer, Niels Weinhold, Marc S Raab, Karsten Rippe
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 6960 (11 29 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 34845188 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Antineoplastic Agents
• Cytokines
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• Receptors, Antigen, T-Cell, gamma-delta

Topics

• Antineoplastic Agents (therapeutic use)
• Bone Marrow (drug effects, immunology, pathology)
• Cytokines (genetics, immunology)
• Drug Resistance, Neoplasm (genetics, immunology)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Gene Regulatory Networks
• Hematopoietic Stem Cells (immunology, pathology)
• Humans
• Intraepithelial Lymphocytes (immunology, pathology)
• Multiple Myeloma (drug therapy, genetics, immunology, pathology)
• Programmed Cell Death 1 Receptor (genetics, immunology)
• Receptors, Antigen, T-Cell, gamma-delta (genetics, immunology)
• Recurrence
• Sequence Analysis, RNA
• Signal Transduction
• Single-Cell Analysis
• Transcriptome
• Tumor Microenvironment (drug effects, genetics, immunology)